With the goal of developing effective topical vaccines, we are currently studying cutaneous (a.k.a., skin-derived) DCs, termed Langerhans cells (LCs). This subset of DCs may have a specialized function in delivering cutaneous antigens to draining lymph nodes where they orchestrate either tolerogenic or immunogenic responses. Recently, we discovered that murine LCs undergo cell death after successful antigen presentation to naive T cells and this limits their immunogenic potential to combat infectious diseases or cancer. We have identified the pertinent apoptosis-signaling cascade used by LCs in response to T cells as "Type II", requiring the pro-apoptotic molecule Bid. In the absence of Bid, LCs are resistant to T cell-induced death as well as mechanisms of UV radiation-induced tolerance and perform as superior vaccinating agents. How such gene-modified, apoptosis-resistant DCs induce enhanced T cell responses, evade induction of regulatory T cells (Treg) development, and the molecular signals used by T cells to trigger DC death are under current investigation.

We have also shown that epidermal keratinocytes depend on Bid expression as a tumor suppressor to protect against the development of UV-induced cutaneous neoplasias. We have evidence that Bid has a novel pro-survival function that may promote cell cycle checkpoints to promote DNA repair after UV damage. We are investigating the novel molecular mechanism by which Bid promotes cell survival in normal and skin tumor cells with the hope of identifying a new pathway that may be important to target with anti-cancer drugs.

In addition, we are developing and testing novel adenoviral vectors that target delivery of genes to dendritic cells and epidermal skin cells to modulate the immune system or ameliorate disease. We are working closely with colleagues in the Gene Therapy Center to test the efficacy of these adenoviral vectors in unique and clinically relevant animal models.